Optical stimulation of 5-HT2A-receptor-expressing neurons in the BNST induces sustained fear in mice

Long-lasting (sustained) fear paradigms have been developed to model clinical situations of patients suffering from long-lasting anxiety disorders. The bed nucleus of the stria terminalis (BNST), as part of the extended amygdala, has been shown to be critically involved in processes of sustained fear response. There is also evidence that 5-HT in BNST affect anxiety-like behaviour (for review see Daniel and Rainnie, 2015). A possible role of 5-HT in the BNST in sustained fear but not short-lasting (phasic) fear responses has been shown earlier by Walker et al. (2009). Specifically, 5-HT2A receptor activity in the BNST might play a major role mediating sustained fear. Through optical stimulation, we test the hypothesis that activation (or silencing) of adBNST 5-HT2A receptors will interfere with of phasic/sustained fear in Htr2a-Cre mice. The aim of the project is to perform optogenetic manipulations in the anterodorsal (ad) BNST with focus on the contribution of 5-HT receptor-mediated processes to phasic/sustained fear to advance the understanding of fear and anxiety-like behavior.

Fear behavior in 5-Htr2a-Cre mice during fear memory retrieval and optical stimulation
(A) Five to six weeks after viral transduction into adBNST (bilaterally), Htr2a-cre mice were conditioned with predictable CS/US timing. 24 hours after fear conditioning, mice were tested in a fear memory retrieval paradigm. (B) Optical stimulation, simultaneously with CS presentation (6 min, horizontal blue bar) during fear memory retrieval induces sustained fear (blue graph), in contrast to controls without optical stimulation (grey). (C)  Verification of viral application site by immunostaining and fluorescencemicroscopy.

Daniel SE and Rainnie DG (2015) Neuropsychopharmacology. doi:10.1038/npp.2015: 1-23.
Walker et al. (2009) Prog Neuropsychopharmacol Biol Psychiatry 33(8): 1291-308.